HomeResearchIntramural ResearchResearch Branches at NHGRIGenetics and Molecular Biology Branch Segre Lab

Julie Segre, Ph.D. Senior Investigator Genetics and Molecular Biology Branch Head Epithelial Biology Section B.A. Amherst College, 1987 Ph.D. Massachusetts Institute of Technology, 1996 (301) 402-2314 (301) 402-4929 jsegre@nhgri.nih.gov Building 49, Room 4A26 49 Convent Dr, MSC 4442 Bethesda, MD 20892-4442 Selected Publications Postdoctoral Fellowship in Genetics & Genomics: Skin and Dermatology

Dr. Segre's research focuses on the dynamic process by which the epidermis maintains a proper balance between proliferation and differentiation. Combining classical genetics techniques and modern genomic tools, her laboratory uses mouse models to investigate the function of novel genes important for in utero human epidermal development, normal wound healing, and skin regeneration.

Located at the interface between the body and its surrounding environment, the epidermis acts as a barrier to infectious agents and protects against the loss of critical bodily fluids. The major barrier activity resides within the exterior layers of the epidermis, which are sloughed off and repopulated from inner cells. This process of differentiation is maintained throughout life as part of epidermal regeneration. However, in infants that are born prematurely, immaturity of the skin, which does not develop its major and necessary function as a barrier until 34 weeks in utero, places them at great risk of disease and early death. This is because their poorly developed epidermis is a portal of entry for infection and potential toxins. Incomplete barrier acquisition by premature infants also can result in dehydration, electrolyte imbalance, and poor thermoregulation.

We discovered the DNA binding protein KLF4, and are investigating the role this protein plays in regulating the development of barrier function. Mice lacking KLF4 protein seem healthy at birth, but die within 15 hours due to rapid water loss through their skin. To analyze the function of KLF4, we identified its downstream targets, which encode proteins that regulate cell proliferation and major components of the cellular "bricks." Our ongoing research examines the role of KLF4's downstream targets in establishing the barrier, the role of pharmacological agents in controlling this process, and the possible interaction between these two pathways.

For humans, maternal injections of glucocorticoids are recommended to accelerate lung and epidermal maturation before an anticipated premature delivery. However, glucocorticoids are extremely potent medications that can be associated with the rapid development of many side effects, including immune suppression, low birth weight, and a host of other metabolic problems. Accordingly, Dr. Segre hopes to discover more specific therapies to replace systemic glucocorticoid treatment for premature births.

To find better strategies for promoting epidermal development, Dr. Segre's group seeks to answer fundamental questions about the mechanism by which epidermal cells produce this barrier. Previously, Dr. Segre discovered that the DNA-binding protein Kruppel-like factor 4 (Klf4) protein was necessary for barrier acquisition. While genetically engineered mice that lacked the Klf4 gene looked identical to normal mice, they lost weight rapidly and died 12 hours after birth; when immersed in a dye solution, these newborn mice absorbed the dye and turned blue, indicating a lack of epidermal barrier development. Dr. Segre's laboratory has demonstrated that ectopic expression of Klf4 in this strain of mice is sufficient to accelerate barrier acquisition, suggesting that Klf4 must be a crucial factor for the skin to achieve barrier function. These genetically engineered mice, therefore, are an important animal model for studying how to accelerate this process in premature infants.

Dr. Segre's laboratory is identifying the downstream targets of both the Klf4 protein and glucocorticoids in the skin so they can test specific molecules that can enhance epidermal barrier acceleration. They also are investigating whether these target genes are coordinately regulated by the Klf4 protein and glucocorticoids. The ultimate goal is to identify genes that have the positive effect of stimulating barrier acquisition without the negative effects of glucocorticoids. In addition to investigating the process of barrier acquisition during embryonic development, Dr. Segre studies the regeneration of the epidermis that occurs with normal wound healing and the skin?s response to other stresses, such as exposure to ultraviolet light and chemicals. Normally, there is an orderly progression of differentiation in the skin. However, when the skin is injured, it activates a stress response that upregulates the expression of structural proteins to erect a temporary barrier until a more permanent one can be built. Her laboratory is investigating whether clusters of genes are held together in the genome to respond in a coordinated fashion to stresses induced by environmental insults.

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Last Reviewed: August 5, 2008